Table 3.

Some molecular targets to therapeutically interrupt necroinflammation

Molecular TargetPrimary EffectCompoundsReference
Regulated necrosis
 RIPK1Stabilizing RIPK1Necrostatins, ponatinib143
 RIPK3Blocking phosphorylation of MLKLGSK872, GSK840144
Dabrafenib145
 pMLKLUnknownNecrosulfonamide146
 Cyclophilin DPreventing mitochondrial membrane potential–related necrosisSanglifehrin A, cyclosporin A35
 PARP1Inhibiting PARP-1–driven parthanatosOlaparib147
 GPX4GPX4 blocks ferroptosis26,27
 Lipid peroxidationLoss of plasma membrane integrityFerrostatins32
Liproxstatin-127
Complement
 C5aBlocking complement-mediated inflammation and injuryEculizumab plus others148151
 ProperdinBlocking alternative complement pathway–related inflammationMAb 1340152
Chemokines/CCRs
 CCL2/CCR2Blocking leukocyte recruitmentNOX-E36, RS504393153,154
 CXCR3Blocking leukocyte recruitmentVUF10085155
 Numerous CKBlocking leukocyte recruitmentTAK-779, NR58–3.14.3155158
Cytokines
 TNF-αBlocking TNF-mediated cell death and inflammationInfliximab plus others110,159161
 IL-1βBlocking IL-1R–mediated immunityAnakinra plus others88,162166
 IL-6Blocking IL-6–mediated immunityTocilizumab plus others167170
 IL-17Blocking IL-17–mediated immunitySecukinumab plus others171173
 Anti-TWEAKBlocking TWEAK-mediated immunityRG7212,174
BIIB023175,176
 Jak-STATBlocking cytokine-driven immunityAG490, S3I-201, ruxolitinib, tofacitinib177,178
179
180
DAMPs
 HistonesBlocking histone cytotoxicity and TLR2/TLR4/NLRP3 activationAntihistone IgG74,92,103
Activated protein C
Heparin
PRRs
 TLR2, TLR4, TLR7, TLR9Blocking TLR-driven immunityOPN-305, IMO-8400181183
 NLRP3Blocking inflammasome-driven IL-1β/IL-18 release and caspase-1–driven pyroptosisGlyburide184
VX-765, MCC950185,186
β-hydroxybutyrate187
  • RIPK1, receptor-activating protein kinase 1; pMLKL, phospho-mixed lineage kinase domain-like protein; PARP-1, poly (ADP-ribose) polymerase 1; GPX4, glutathione peroxidase 4; CCR, chemokine (C-C motif) receptor; CCL, chemokine (C-C motif) ligand; CXCR3, chemokine (C-X-C motif) receptor 3; CK, chemokines; TWEAK, TNF-like weak inducer of apoptosis; Jak-STAT, Janus kinase and Signal Transducer and Activator of Transcription; PRR, pattern recognition receptors; MAb, monoclonal antibody.